Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization

Abstract

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results:We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion:Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

Liposome–trimethyl chitosan nanoparticles codeliver insulin and siVEGF to treat corneal alkali burns by inhibiting ferroptosis

“…CNV is a severe complication of corneal injury that not only affects the transparency and avascular nature of the cornea but also makes the cornea more vulnerable to inflammatory reactions. 48 To did not inhibit neovascularization in alkali-burned corneas. This may be because oxidative stress and inflammatory reactions first occur in alkali-burned corneas, and then they stimulate angiogenic factors and promote neovascularization.…”

“…CNV is a severe complication of corneal injury that not only affects the transparency and avascular nature of the cornea but also makes the cornea more vulnerable to inflammatory reactions 48 . To verify the ability of NPs to inhibit neovascularization, VEGF protein expression was measured by WB analysis.…”

Functional Peptide-Loaded Gelatin Nanoparticles as Eyedrops for Cornea Neovascularization Treatment

“…The corneal NV mice model was induced as previous study. 34 Briefly, the mice were anesthetized and immobilized before examination. Next, topical administration of Alcaine (Alcon, Puurs, Belgium) for local anesthesia, followed by pressing the tip of an applicator containing silver nitrate/potassium (25%/75%, Grafco, Atlanta, GA, USA) to the center of the cornea steadily for eight seconds.…”

Chemical and Structural Engineering of Gelatin-Based Delivery Systems for Therapeutic Applications: A Review

“…111,112 Wang et al employed a two-step desolvation method to prepare GNPs encapsulating 5z-7-oxozeaenol (GNPs-Oxo) for the treatment of corneal neovascularization (CoNV). 113 The resulting gelatin nanoparticles exhibited a size of approximately 97 nm (Figure 9a). These GNPs loaded with Oxo were shown to reduce the angiogenesis process by inhibiting cell proliferation and enhancing angiogenic activities, including endothelial migration and tube formation.…”